CN1853625A - Combination of sweet-scented osmanthus and plantinum chemotherapeutic medicine - Google Patents
Combination of sweet-scented osmanthus and plantinum chemotherapeutic medicine Download PDFInfo
- Publication number
- CN1853625A CN1853625A CN 200610074209 CN200610074209A CN1853625A CN 1853625 A CN1853625 A CN 1853625A CN 200610074209 CN200610074209 CN 200610074209 CN 200610074209 A CN200610074209 A CN 200610074209A CN 1853625 A CN1853625 A CN 1853625A
- Authority
- CN
- China
- Prior art keywords
- sweet
- scented osmanthus
- luteolin
- platinum
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
An application of the luteolin in preparing the medicine by combining it with the Pt-type chemicotherapeutic medicine chosen from cisplatin, oxaliplatin and carboplatin for treating tumor is disclosed. Said composite medicine is also disclosed.
Description
Technical field
The present invention relates to be used for the compositions that antineoplastic is made up of a kind of flavone compound and a kind of platinum-based chemotherapy medicine; The invention still further relates to the purposes of this chemical compound in the medicine of preparation treatment tumor.
Background technology
" chemotherapy " is the abbreviation of " chemotherapy ".The notion of chemotherapy generally is understood that " chemotherapy of tumor " at present, promptly uses antineoplastic chemotherapy medicine, adopts the method for some measure and scheme treatment tumor.Wherein " platinum antineoplastic chemotherapeutics " has mutually similar antitumor action mechanism: the significant feature target spot is positioned at DNA, can be crosslinked in the DNA vessel used to hold grain at the imperial sacrifice by forming, interchain linkage, DNA-protein cross, destroy duplicating and suppressing the growth that cell division etc. is used for suppressing tumor cell of DNA.Common has: and cisplatin (cisplatin CDDP), carboplatin (carboplatin), oxaliplatin (oxaliplatin, JM-216, L-OH), nedaplatin (nedaplatin), network platinum (lobaplatin) etc.They have similar antitumor pharmacology mechanism as similar chemotherapeutics, and similar toxic and side effects is also arranged.
Yet common chemotherapeutics such as vincristine, cisplatin, methotrexate, cyclophosphamide, 5-fluorouracil (5-Fu) etc. can produce toxic and side effects such as injection site pain, venous thrombosis, bone marrow depression, gastrointestinal reaction, peripheral nervous pathological changes.
For the toxic and side effects that reduces chemotherapeutics, improve curative effect, reduce tumor recurrence and avoid drug-fast generation, selects different chemotherapy drugs in combination uses, become one of important means of chemotherapy of tumors.For example, clinically cisplatin and 5-Fu, bleomycin or epipodophyllotoxin etc. are united the use treatment esophageal carcinoma.
The curative effect sum of the curative effect that " synergism " (Synergistic Effect) produced when being meant two kinds of medication combined use when two prescriptions solely use during greater than same dose.According to middle effect principle (Joseph R.Bertino, Ting-Chao Chou, Chemotherapy:Synergism and Antagonism, Encyclopedia of Cancer, 1996, Academic Press, Inc.), two medicines unite action effect when using can pass through " association index " (Combination Index, CI) judge:
Wherein, when D1, D2 are respectively medicine 1 and medicine 2 independent uses, the drug level when cell proliferation inhibition rate reaches x%; (Dx) 1, the concentration of (Dx) 2 mixture Chinese medicine 1 and medicine 2 when reaching the same cell proliferation inhibition rate.
To two kinds of separate medicine α=0; And medicine α=1 independently not mutually.
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Because animal vivo test is difficult to the outer test method of analog, i.e. multiple dose, the drug effect pattern of many concentration.So be difficult to obtain CI numerical value.So those of ordinary skill in the art also has the Q-value that adopts the Jin Shi formula to calculate and statistical procedures after the significant difference that obtains to have deny that (p value) is used as judgement (Dai Tijun to animal test results, the Chinese Pharmacological circular, 1998,14 (5): 479-480):
Q＝E(a+b)/Ea+Eb(1-Ea)；
Wherein E is a tumour inhibiting rate, when Q＜0.85 is an antagonism, is addition between Q0.85～1.15, and Q＞1.15 are for collaborative.
The animal experiment pattern that the antitumorigenic substance of establishing in nineteen eighty-three according to national cancer institute screens, be used for having of the interior transplanted tumor strain of mice body: mouse melanin glucagonoma cell strain B16, solid tumor (entity tumor) tumor strains such as mice fibrosarcoma cell strain M5076; Blood such as mouse leukemia cell strain L1210 are the strain of tumor tumor.So those of ordinary skill in the art to adopt and selects for use certain tumor tumor strain to be used as animal vivo test pattern at transplantation tumor: as select for use the mice animal experiment of mouse melanin glucagonoma cell strain B16 to be used as animal vivo test pattern at entity tumor; Selecting for use the mice animal experiment of mouse leukemia cell strain L1210 to be used as at blood is the animal vivo test pattern of tumor.Judge by result of the test inside and outside the coalition whether test substance has antitumor action.
Luteolin (another name: xanthein, cyanidenon etc.; English name: Luteolin), belong to flavone compound, can from some plants such as Flos Lonicerae, Flos Chrysanthemi etc., extract and obtain.Be yellow crystals, molecular weight 286.2, fusing point: 328 ℃-330 ℃, be slightly soluble in water, be dissolved in aqueous slkali.Structural formula is as follows:
According to the literature, luteolin has antioxidation, antibiotic, antiinflammatory, anticancer, spasmolytic, eliminates the phlegm, presses down the effect of enzyme, diuresis function of gallbladder promoting.
Do not see that so far relevant luteolin and chemotherapeutics have synergistic report on antitumor.
Summary of the invention
Appearance of the present invention partly is based on so unexpected discovery: luteolin and a kind of platinum-based chemotherapy medicine comprise that cisplatin, oxaliplatin and carboplatin have the synergistic antitumor effect; A kind of medicine can produce stronger antitumor action compared with singly using wherein to unite use luteolin and a kind of platinum-based chemotherapy medicine such as cisplatin, oxaliplatin or carboplatin.
The present invention relates to a kind of luteolin or its officinal salt and comprise that at preparation a kind of and platinum-based chemotherapy medicine cisplatin, oxaliplatin and carboplatin unite with the purposes in the medicine of treatment tumor.
Second aspect of the present invention relates to a kind of antitumor medicine composition, comprises luteolin and a kind of platinum-based chemotherapy medicine.
The invention still further relates to a kind of method for the treatment of tumor, it comprises a kind of platinum-based chemotherapy medicine and the luteolin compositions of the mammal use effective dose that needs are treated.
The specific embodiment of the present invention will set forth with the lower part.Other characteristics of the present invention, purpose and advantage will be shown by following elaboration.
The specific embodiment:
The inventor discovers, when luteolin of the present invention and a kind of platinum-based chemotherapy medicine include but not limited to: cisplatin, oxaliplatin or carboplatin can obviously improve both anti-tumor activities successively or during administration simultaneously, have synergism; Thereby can reduce both consumptions, reduce its toxic and side effects.Therefore, luteolin of the present invention and a kind of platinum-based chemotherapy medicine include but not limited to: cisplatin, oxaliplatin or carboplatin can be united use with the treatment tumor.
As used herein, term " treatment " are meant that the mammal that gives to treat based on the purpose of curing, alleviating, improving, alleviating, influencing treatment target disease, symptom, disease body constitution (predisposition) is united and use luteolin of the present invention and a kind of platinum-based chemotherapy medicine.
Term " officinal salt " comprises various inorganic or acylate example hydrochloric acid salt, hydrobromate, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates; (TRIS is tromethane) with N-methyl-glucamine for various inorganic or organic alkali salts such as sodium hydroxide, Tris.
The technology contents of institute of the present invention incorporated by reference data is incorporated herein by reference in the lump with regard to its integral body.
Luteolin of the present invention can extract from plants such as Flos Lonicerae, Flos Chrysanthemi and obtain.Luteolin of the present invention also can obtain or common synthetic technology by this area makes or makes by action of microorganisms by commercial sources.Be used to separate or the chemicals of synthetic luteolin of the present invention comprises solvent, reagent, catalyst, blocking group reagent, removes blocking group reagent.Described separation can also comprise adding or remove suitable blocking group finally to obtain the step of required luteolin with synthetic.The synthetic chemistry that is used to prepare luteolin of the present invention transforms and the method for radical protection (going to protect) is known to those skilled in the art, can be referring to R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Green and P.G.M.Wuts, Protective Groups in Organic Synthesis, 3
RdEd., John Wiley and Sons (1999), L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents forOrganic Synthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995) and follow-up works thereof.
The present invention relates to use the Therapeutic Method of the compositions of two kinds of compositions (luteolin and a kind of platinum-based chemotherapy medicine include but not limited to: cisplatin, oxaliplatin or carboplatin).These two kinds of compositions can be simultaneously or administration successively, or luteolin and a kind of platinum-based chemotherapy medicine are made a kind of pharmaceutical composition use in a kind of pharmaceutically suitable carrier.The composition of this pharmaceutical composition can any intestinal easily or the dosage form administration separately or together of parenteral route administration.The intestinal canal administration preparation includes but not limited to: capsule, tablet, Emulsion, aqueous suspension agent, colloidal solution, solution, microcapsule, pill, lozenge, granule, powder.The pharmaceutically suitable carrier that is usually used in capsule comprises lactose and dried corn starch.The pharmaceutically suitable carrier that is usually used in tablet comprises lactose and corn starch, also can add lubricants such as magnesium stearate usually.When making oral aqueous suspension agent and/or Emulsion, pharmaceutical composition of the present invention can suspend or be dissolved in the oil phase and with emulsifying agent or suspending agent and combine.If desired, also can add some sweeting agents and/or flavouring agent and/or toner.
That the parenterai administration approach comprises is subcutaneous, in the Intradermal, tremulous pulse, vein, muscle, joint, synovial fluid, breastbone, sheath, intralesional, intracranial injection or instillation.Other route of administration can comprise part, rectum, per nasal, through cheek, vagina, Sublingual, mucosa, trachea or urethra.In addition, pharmaceutical composition of the present invention can also suck or implant and accumulate or mode administration such as acupuncture by aerosol.
Pharmaceutical composition of the present invention can be made into aseptic injection, as aseptic water or oil phase suspension.This suspension can use suitable dispersant or wetting agent (as Tween 80) and suspending agent etc. to make by the conventional method of this area.But it can also be at the nontoxic diluent of intestinal external administration or aqueous solution or the suspension in the solvent, as the solution in 1,3 butylene glycol.Relevant available support or solvent comprise mannitol, water, ringer's solution, isotonic sodium chloride etc., also may contain solubilizing agents such as soil temperature class or propylene glycol.In addition, aseptic fixedly oil (bland fixed oil) often is used as the media of solvent or suspending agent, thereby comprises that the multiple soft fixedly oil of synthetic glycerine monoesters or diglyceride all is suitable for.Fatty acid can be used for preparing described injection as octadecenic acid and glyceride ester derivatives thereof (as olive oil or Oleum Ricini, particularly its polyoxyethylene radical derivative) etc.Described oil solution or suspension also can comprise a kind of ethanol dilution agent of long-chain or dispersant or carboxymethyl cellulose or similar other dispersants, and this type of material is usually used in preparing pharmaceutical acceptable emulsion and/or suspending agent.Surfactant that some other preparation is commonly used such as Tweens or Spans and/or other similar emulsifying agents or bioavailability promoter etc. can be used for preparing preparation of the present invention too.
Pharmaceutical composition of the present invention can be made into suppository and passes through rectally, method is that pharmaceutical composition of the present invention is mixed with the non-irritating excipient that suits, the latter is liquid under rectal temperature for solid at room temperature, thereby this suppository is dissolvable in water in the rectum and discharges active ingredient.This type of excipient includes but not limited to: cupu oil, Cera Flava and polyethylene.The local administration preparation of pharmaceutical composition of the present invention (as ointment) can be directly used in the affected part.This type of topical formulations contains active ingredient and pharmaceutically suitable carrier, and the latter includes but not limited to: mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene or the polyoxy third desaturation compound, emulsifying is cured or water.In addition, pharmaceutical composition of the present invention also can be made into lotion or oil preparation.The carrier that is suitable for includes but not limited to: mineral oil, sorbic alcohol monostearate, polysorbate60, spermaceti ester, hexadecanol, 2-octadecanol, benzyl ethanol or water.Pharmaceutical composition of the present invention also can be made into enema etc. and is used for the rectum topical.
The topical transdermal patch is also within protection scope of the present invention.But pharmaceutical composition of the present invention is per nasal spraying or inhalation also, promptly by the conventional method of this area, uses benzyl ethanol or other antiseptic, absorption enhancer, fluorocarbon and/or other solubilizing agents or dispersant to make saline solution.
Pharmaceutical composition of the present invention also can pass through drug delivery implant.Adopt the drug delivery implant mode can reach in the administration subject and continue, regularly discharge the effect of pharmaceutical composition of the present invention.In addition, drug delivery implant can also be at local organization and organ site-specific delivery of drugs (Negrin et al., Biomaterials 22 (6): 563,2001) regularly release tech also can be used in the administration of pharmaceutical composition of the present invention, as delayed release capsule, slow release method and the preparation technique for packing (as polymer and liposome) etc. based on the polymer technology.
Patch is included within protection scope of the present invention equally.It comprises basic unit's (as polymer, cloth, yarn and binder) and pharmaceutical composition of the present invention.One side of basic unit can be provided with a protective layer to prevent the outflow of active ingredient.Described patch also can contain a binding agent that is used for fixing, and the latter can be a kind of natural or synthetic material, can temporarily adhere on the skin when it contacts with the administration subject's skin.Binding agent can be a waterproof.
" pharmaceutically suitable carrier " can not destroy the pharmaceutical active of pharmaceutical composition of the present invention, its effective dose simultaneously, and promptly can playing pharmaceutical carrier, to make the consumption of time spent nontoxic to human body." pharmaceutically suitable carrier " includes but not limited to: ion exchange material, aluminium oxide, aluminium stearate, lecithin, self-emulsifying drug delivery system (SEDDS) is as d-alpha-tocopherol cetomacrogol 1000 succinate, the surfactant that pharmaceutical preparatioies such as tween (Tweens) or other similar polymerisation mediums are used, serum albumin such as human serum albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glycerol ester admixture, water, salt, electrolyte such as sulfate protamine, phosphoric acid hydrogen two is received, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate etc.Polyvidon, cellulosic material, polyvinyl alcohol, sodium carboxymethyl cellulose, polypropylene acid esters, ethylene-polyoxyethylene-block polymer and wool grease, cyclodextrin such as α-, β-and gamma-cyclodextrin or its all can be used for promoting the drug delivery of pharmaceutical composition of the present invention through hydroxyalkyl cyclodextrin such as the derivant of chemical modification such as 2-and 3-HP-or other soluble derivatives etc.
The luteolin that pharmaceutical composition of the present invention is contained and a kind of platinum-based chemotherapy medicine include but not limited to: the synergistic effective range (molar concentration rate) of cisplatin, oxaliplatin or carboplatin is verified by suitable in vitro tests (in vitro assay).As a kind of tumor chemotherapeutic drug commonly used, the conventional amount used and the route of administration of cisplatin, carboplatin and oxaliplatin are as follows: cisplatin 15-35 milligram/square metre (body surface area) continuous use a few days also has 70-100 milligram/square metre single medication; Time a few days administration of carboplatin 300-400 milligram/square metre single medication or mark; Oxaliplatin 85-135 milligram/square metre single medication.The bibliographical information of clinical antitumor dosage of the relevant luteolin of Shang Weijian and suitable route of administration thereof.The accurate consumption of any composition can wait to determine according to the effectiveness of compound used therefor, patient's age, body weight, health and patient's sensitivity in the clinical practice use in the employed compositions.Those of ordinary skill in the art also should know how to pass through the ordinary skill in the art, according to molar concentration rate disclosed by the invention, luteolin and cisplatin, oxaliplatin or carboplatin are mixed, prepare the pharmaceutical composition with oncotherapy effect of the present invention.
For the ease of understanding the present invention, the spy enumerates following examples.Its effect should be understood that it is to annotation of the present invention and absolutely not to any type of restriction of the present invention.
Embodiment 1 luteolin is to the synergism of cisplatin (CDDP) on anti-hepatoma carcinoma cell
Human hepatoma cell strain HepG2 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin, and mix in the adding culture fluid with different molar concentration rates with cisplatin.Ultimate density: luteolin 0.3-200 μ g/ml, cisplatin: 0.3-3 μ g/ml.Continue again to cultivate and make MTT mensuration after 72 hours.To HepG2 inhibition of proliferation rate, carry out data analysis during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and cisplatin with CalcuSyn statistical software and drug combination exponential quantity (CI) method.
HepG2 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 1:
Table 1
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 1 | 15±2.2 | ||
| Sweet-scented osmanthus 2 | 27.75±3 | ||
| Sweet-scented osmanthus 4 | 50.7±3 | ||
| Sweet-scented osmanthus 8 | 72.5±3.2 | ||
| Sweet-scented osmanthus 16 | 87.2±3.1 | ||
| Pt1 | 15.2±2 | ||
| Pt2 | 32.8±3 |
| Pt4 | 40.9±3.5 | ||
| Pt8 | 72.9±3 | ||
| Pt1+ sweet-scented osmanthus 1 | 31.9±2.3 | 0.9 | |
| Pt2+ sweet-scented osmanthus 2 | 55±2 | 0.85 | |
| Pt4+ sweet-scented osmanthus 4 | 95±2 | 0.2 | |
| Pt8+ sweet-scented osmanthus 8 | 99±3.5 | 0.11 | |
| Pt1+ sweet-scented osmanthus 2 | 47.9±2 | 0.8 | |
| Pt2+ sweet-scented osmanthus 4 | 75.75±3 | 0.63 | |
| Pt4+ sweet-scented osmanthus 8 | 99±3.7 | 0.1 | |
| Pt1+ sweet-scented osmanthus 4 | 70.82±3.2 | 0.65 | |
| Pt2+ sweet-scented osmanthus 8 | 92±3.5 | 0.3979 | |
| Pt4+ sweet-scented osmanthus 16 | 99±2.9 | 0.155 | |
| Pt8+ sweet-scented osmanthus 32 | 99±3.8 | 0.311 | |
| Pt1+ sweet-scented osmanthus 10 | 92±3 | 0.447 | |
| Pt2+ sweet-scented osmanthus 20 | 99±2 | 0.177 | |
| Pt4+ sweet-scented osmanthus 40 | 99±3 | 0.36 |
Annotate: sweet-scented osmanthus=luteolin; Pt=cisplatin (CDDP)
Conclusion:
Table 1 shows luteolin and cisplatin (CDDP) to the HepG2 drug combination time, when the molar concentration rate of cisplatin and luteolin is 1: 1,1: 2,1: 4, presents good synergistic action effect at 1: 10 o'clock.
Embodiment 2 luteolins are to the synergism of cisplatin (CDDP) on anti-lung carcinoma cell
Human lung carcinoma cell line A549 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin, and mix in the adding culture fluid with different molar concentration rates with cisplatin.Ultimate density: luteolin 0.3-200 μ g/ml, cisplatin: 0.3-3 μ g/ml.Continue again to cultivate and make MTT mensuration after 72 hours.To A549 inhibition of proliferation rate, carry out data analysis during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and cisplatin with CalcuSyn statistical software and drug combination exponential quantity (CI) method.
A549 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 2:
Table 2
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 4.01±3 | ||
| Sweet-scented osmanthus 5 | 10.01±3.2 | ||
| Sweet-scented osmanthus 10 | 28.03±4.1 | ||
| Sweet-scented osmanthus 20 | 49.37±3.7 | ||
| Sweet-scented osmanthus 40 | 68.67±3 | ||
| Pt1 | 0.01±2 | ||
| Pt2 | 29.8±3.2 | ||
| Pt4 | 32.85±3.7 | ||
| Pt8 | 44.1±2.9 | ||
| Pt1+ sweet-scented osmanthus 2.5 | 23.53±3.5 | 0.55 | |
| Pt2+ sweet-scented osmanthus 5 | 64.22±3.2 | 0.38 | |
| Pt4+ sweet-scented osmanthus 10 | 73.11±2.7 | 0.5957 | |
| Pt8+ sweet-scented osmanthus 20 | 88.5±4.1 | 0.6475 | |
| Pt1+ sweet-scented osmanthus 5 | 37.33±3.2 | 0.534 | |
| Pt2+ sweet-scented osmanthus 10 | 75±3.2 | 0.48 | |
| Pt4+ sweet-scented osmanthus 20 | 77.7±3.9 | 0.7126 | |
| Pt8+ sweet-scented osmanthus 40 | 90.7±2.5 | 0.7584 | |
| Pt1+ sweet-scented osmanthus 10 | 62.7±2.9 | 0.4429 | |
| Pt2+ sweet-scented osmanthus 20 | 70±3 | 0.7168 | |
| Pt4+ sweet-scented osmanthus 40 | 85±2.7 | 0.81 |
Annotate: sweet-scented osmanthus=luteolin; Pt=cisplatin (CDDP)
Conclusion:
Table 2 shows that luteolin and cisplatin (CDDP) to the A549 drug combination time, present good synergistic action effect when the molar concentration rate of cisplatin and luteolin is 1: 2.5,1: 5,1: 10.
Embodiment 3 luteolins are to the synergism of cisplatin (CDDP) on anti-stomach cancer cell
Human stomach cancer cell line MKN28 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin, and mix in the adding culture fluid with different molar concentration rates with cisplatin.Ultimate density: luteolin 0.3-200 μ g/ml, cisplatin: 0.3-3 μ g/ml.Continue again to cultivate and make MTT mensuration after 72 hours.To MKN28 inhibition of proliferation rate, carry out data analysis during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and cisplatin with CalcuSyn statistical software and drug combination exponential quantity (CI) method.
MKN28 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 3:
Table 3
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 0.34±2 | ||
| Sweet-scented osmanthus 5 | 0.9±2 | ||
| Sweet-scented osmanthus 10 | 46.2±3.2 | ||
| Sweet-scented osmanthus 20 | 67.22±2.7 | ||
| Sweet-scented osmanthus 40 | 80.88±3.2 | ||
| Pt1 | 16.32±3.5 | ||
| Pt2 | 18.83±3.7 | ||
| Pt4 | 38.01±3.5 | ||
| Pt8 | 61.51±4.2 | ||
| Pt1+ sweet-scented osmanthus 2.5 | 15.92±3 | 1.087 | |
| Pt2+ sweet-scented osmanthus 5 | 21.84±3.2 | 1.56 | |
| Pt4+ sweet-scented osmanthus 10 | 56.6±2 | 1.02 | |
| Pt8+ sweet-scented osmanthus 20 | 87.3±3.7 | 0.778 | |
| Pt1+ sweet-scented osmanthus 5 | 27±3.8 | 0.829 | |
| Pt2+ sweet-scented osmanthus 10 | 53.9±3 | 0.816 | |
| Pt4+ sweet-scented osmanthus 20 | 75.1±2 | 0.98 | |
| Pt8+ sweet-scented osmanthus 40 | 93.52±2 | 0.9672 | |
| Pt1+ sweet-scented osmanthus 10 | 60.33±3.2 | 0.479 |
| Pt2+ sweet-scented osmanthus 20 | 73.04±2.3 | 0.91 | |
| Pt4+ sweet-scented osmanthus 40 | 93±3.3 | 0.95 |
Annotate: sweet-scented osmanthus=luteolin; Pt=cisplatin (CDDP)
Conclusion:
Table 3 show luteolin with cisplatin (CDDP) to the MKN28 drug combination time, when the molar concentration rate of cisplatin and luteolin is 1: 2.5,1: 5,1: 10, present good synergistic action effect.
Embodiment 4 luteolins are to the synergism of cisplatin (CDDP) in Chinese People's Anti-Japanese Military and Political College's colon-cancer cell strain
Human large intestine cancer cell strain HCT116 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin, and mix in the adding culture fluid with different molar concentration rates with cisplatin.Ultimate density: luteolin 0.3-200 μ g/ml, cisplatin: 0.3-3 μ g/ml.Continue again to cultivate and make MTT mensuration after 72 hours.To HCT116 inhibition of proliferation rate, carry out data analysis during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and cisplatin with CalcuSyn statistical software and drug combination exponential quantity (CI) method.
HCT116 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 4:
Table 4
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 8±2 | ||
| Sweet-scented osmanthus 5 | 19.1±3 | ||
| Sweet-scented osmanthus 10 | 37.7±3 | ||
| Sweet-scented osmanthus 20 | 49±3.2 | ||
| Sweet-scented osmanthus 40 | 56.85±3.5 | ||
| Pt1 | 15±3.8 | ||
| Pt2 | 30.1±3 | ||
| Pt4 | 48.3±4.2 | ||
| Pt8 | 70.85±3.8 | ||
| Pt1+ sweet-scented osmanthus 2.5 | 10.85±2.3 | 2.255 | |
| Pt2+ sweet-scented osmanthus 5 | 48.1±3.5 | 0.76 |
| Pt4+ sweet-scented osmanthus 10 | 75.1±2.5 | 0.55 | |
| Pt8+ sweet-scented osmanthus 20 | 92.8±2.9 | 0.32 | |
| Pt1+ sweet-scented osmanthus 5 | 39.2±2.8 | 0.689 | |
| Pt2+ sweet-scented osmanthus 10 | 63±3 | 0.575 | |
| Pt4+ sweet-scented osmanthus 20 | 79.6±2 | 0.55 | |
| Pt8+ sweet-scented osmanthus 40 | 89.2±2.5 | 0.568 | |
| Pt1+ sweet-scented osmanthus 10 | 61±3 | 0.447 | |
| Pt2+ sweet-scented osmanthus 20 | 74.11±2.9 | 0.51 | |
| Pt4+ sweet-scented osmanthus 40 | 88±2 | 0.429 |
Annotate: sweet-scented osmanthus=luteolin; Pt=cisplatin (CDDP)
Conclusion:
Table 4 show luteolin with cisplatin (CDDP) to the HCT116 drug combination time, when the molar concentration rate of cisplatin and luteolin at 1: 2.5,1: 5, presented good synergistic action effect at 1: 10 o'clock.
Embodiment 5 luteolins are to the synergism of cisplatin (CDDP) on anti-esophageal carcinoma
People's esophageal cancer cell strain TE2 is suspended in cell strain in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin, and mix in the adding culture fluid with different molar concentration rates with cisplatin.Ultimate density: luteolin 0.3-200 μ g/ml, cisplatin: 0.3-3 μ g/ml.Continue again to cultivate and make MTT mensuration after 72 hours.To HE2 inhibition of proliferation rate, carry out data analysis during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and cisplatin with CalcuSyn statistical software and drug combination exponential quantity (CI) method.
TE2 cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 5:
Table 5
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 7.4±2 |
| Sweet-scented osmanthus 5 | 17.8±3 | ||
| Sweet-scented osmanthus 10 | 45±4.2 | ||
| Sweet-scented osmanthus 20 | 67.75±3.2 | ||
| Sweet-scented osmanthus 40 | 79.22±2.8 | ||
| Pt1 | 15.2±3 | ||
| Pt2 | 30.37±2.7 | ||
| Pt4 | 45.8±3 | ||
| Pt8 | 72.1±3 | ||
| Pt1+ sweet-scented osmanthus 2.5 | 22.5±2.5 | 1.1 | |
| Pt2+ sweet-scented osmanthus 5 | 64.8±2.7 | 0.5472 | |
| Pt4+ sweet-scented osmanthus 10 | 73.02±3.2 | 0.82 | |
| Pt8+ sweet-scented osmanthus 20 | 92.1±2 | 0.5477 | |
| Pt1+ sweet-scented osmanthus 5 | 49.15±2 | 0.6325 | |
| Pt2+ sweet-scented osmanthus 10 | 76.7±3 | 0.515 | |
| Pt4+ sweet-scented osmanthus 20 | 86.2±3.2 | 0.6446 | |
| Pt8+ sweet-scented osmanthus 40 | 92.1±2.9 | 0.81 | |
| Pt1+ sweet-scented osmanthus 10 | 72.25±3.5 | 0.497 | |
| Pt2+ sweet-scented osmanthus 20 | 81.86±3.7 | 0.669 | |
| Pt4+ sweet-scented osmanthus 40 | 95±2 | 0.4786 |
Annotate: sweet-scented osmanthus=luteolin; Pt=cisplatin (CDDP)
Conclusion:
Table 5 show luteolin with cisplatin (CDDP) to the TE2 drug combination time, when the molar concentration rate of cisplatin and luteolin at 1: 2.5,1: 5, presented good synergistic action effect at 1: 10 o'clock.
Embodiment 6 luteolin combination with cisplatin (CDDP) are to the antitumor synergism of transplanted tumor
With the strain of B16 melanoma cell at In vitro culture after two generations, with 2 * 10
6Cell/only the be inoculated in female C57BL/6 of laboratory animal (body weight is about 20 grams) mice oxter is subcutaneous.Inoculate back second day random packet, and begin administration by the 0.1ml/10g body weight.Luteolin (Shaanxi plant development corporation, Ltd. of intelligent section), and with cisplatin (Sigma company product) with individually dosed, the test of different administering mode such as administering drug combinations grouping carrying out antitumor.Every group laboratory animal is 10.Measure the weight of animals before the administration, test and took off neck execution behind the title the weight of animals on 15th, strip tumor block organization and weigh.The mensuration of tumour inhibiting rate is by computing formula; Tumour inhibiting rate=(1-treatment group tumor weight/blank group tumor is heavy) * 100% calculates the heavy suppression ratio of tumor and carries out statistics (t check) and handle.And calculate Q-value according to the Jin Shi formula.
Result of the test sees Table 6:
Table 6 separately when medication and combination with cisplatin medication to transplanting the melanomatous animal test results of B16
Sweet-scented osmanthus=luteolin
| Grouping | Dosage mg/kg | The administration schedule | The rate of losing weight % | Heavy (g) the mean value SD of tumor | Tumour inhibiting rate % | Number of animals (only) beginning/end |
| Control group cis-platinum sweet-scented osmanthus sweet-scented osmanthus sweet-scented osmanthus cis-platinum+sweet-scented osmanthus cis-platinum+sweet-scented osmanthus cis-platinum+sweet-scented osmanthus | - 2 5 10 20 2+5 2+10 2+20 | 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 | ＜0 ＜5 ＜5 ＜5 ＜5 ＜5 ＜5 ＜5 | 2.65±0.22 1.59±0.28 2.535±0.22 2.328±0.15 2.035±0.10 1.33±0.07 1.27±0.09 1.118±0.119 | 40 4.3 12.15 23.2 49.8 *## 52 **## 57.8 **# | 10/10 10/10 10/10 10/10 10/10 10/10 10/10 10/10 |
Administering mode: cisplatin; The abdominal cavity, luteolin; Intraperitoneal administration
*Compare P＜0.05 with single with the cisplatin group
*Compare P＜0.01 with single with the cisplatin group
The #Q value shows summation action
The ##Q value shows synergism
Visible luteolin of result of the test and cisplatin have embodied tangible antitumor potentiation when share.Cisplatin+luteolin 5mg/kg, cisplatin+luteolin 10mg/kg, each group of cisplatin+luteolin 20mg/kg all has significant difference on the statistics with single comparing with the cisplatin group.Q-value also demonstrates has addition and synergism.Animal test results has been supported the result of in vitro tests significantly, and promptly near luteolin and the cisplatin zone 1: 2.5～1: 10 concentration ratio has apparent in view collaborative medication effect.Change and can see from the weight of animals, each combination group is not seen has any toxicity to strengthen trend.
Comprehensive animal experiment as seen; Luteolin and cisplatin have good synergistic antitumor effect.
The synergism that embodiment 7 luteolins associating oxaliplatins (JM-216) suppress in the human tumor cell line growth in vitro
With all kinds of human tumor cell line cell suspensions in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin (Shaanxi plant development corporation, Ltd. of intelligent section), and add in the culture fluid than mixing with variable concentrations with oxaliplatin (Sigma company product).Cultivate and make MTT mensuration after 72 hours.The suppression ratio of on cell proliferation carries out data analysis with CalcuSyn statistical software and drug combination exponential quantity (CI) method during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and oxaliplatin.When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Each human tumor cell line is: human large intestine cancer cell HCT116 table 7
Human lung carcinoma cell line A549 table 8
Human stomach cancer cell line MKN45 table 9
Cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 7:
HCT116 cell increment suppression ratio when independent medication of table 7 luteolin and the medication of associating oxaliplatin, and unite usefulness
The medicine index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 7±2.7 | ||
| Sweet-scented osmanthus 5 | 18±3 | ||
| Sweet-scented osmanthus 10 | 38.7±4.1 | ||
| Sweet-scented osmanthus 20 | 57±3.5 | ||
| Sweet-scented osmanthus 40 | 67±2.7 | ||
| Platinum 1 difficult to understand | 32.2±3.2 | ||
| Platinum 2 difficult to understand | 49.7±2.9 | ||
| Platinum 4 difficult to understand | 59.8±3.2 | ||
| Platinum 8 difficult to understand | 67±3.2 | ||
| Platinum 1+ sweet-scented osmanthus 5 difficult to understand | 42±2.2 | 1 | |
| Platinum 2+ sweet-scented osmanthus 10 difficult to understand | 67.7±2.9 | 0.574 |
| Platinum 4+ sweet-scented osmanthus 20 difficult to understand | 82.2±3.5 | 0.487 | |
| Platinum 8+ sweet-scented osmanthus 40 difficult to understand | 92±2 | 0.387 | |
| Platinum 0.5+ sweet-scented osmanthus 5 difficult to understand | 39±2 | 0.785 | |
| Platinum 1+ sweet-scented osmanthus 10 difficult to understand | 57±3 | 0.705 | |
| Platinum 2+ sweet-scented osmanthus 20 difficult to understand | 79.8±3.2 | 0.465 | |
| Platinum 4+ sweet-scented osmanthus 40 difficult to understand | 90.2±2.9 | 0.418 | |
| Platinum 0.5+ sweet-scented osmanthus 7.5 difficult to understand | 45.2±3.2 | 0.753 | |
| Platinum 1+ sweet-scented osmanthus 15 difficult to understand | 75.8±3.2 | 0.4 | |
| Platinum 2+ sweet-scented osmanthus 30 difficult to understand | 92.8±2.8 | 0.221 |
A549 cell increment suppression ratio when independent medication of table 8 luteolin and the medication of associating oxaliplatin, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 4.01±3 | ||
| Sweet-scented osmanthus 5 | 10.01±3.2 | ||
| Sweet-scented osmanthus 10 | 28.03±4.1 | ||
| Sweet-scented osmanthus 20 | 49.37±3.5 | ||
| Sweet-scented osmanthus 40 | 68.67±2.7 | ||
| Platinum 1 difficult to understand | 27.8±3.1 | ||
| Platinum 2 difficult to understand | 39±3.9 | ||
| Platinum 4 difficult to understand | 50.2±3.5 | ||
| Platinum 8 difficult to understand | 79±3.2 | ||
| Platinum 0.5+ sweet-scented osmanthus 2.5 difficult to understand | 15±3.2 | 1.288 | |
| Platinum 1+ sweet-scented osmanthus 5 difficult to understand | 32±3.9 | 1.1 | |
| Platinum 2+ sweet-scented osmanthus 10 difficult to understand | 62±3.2 | 0.77 | |
| Platinum 4+ sweet-scented osmanthus 20 difficult to understand | 87±2.9 | 0.481 | |
| Platinum 0.5+ sweet-scented osmanthus 5 difficult to understand | 17±2.8 | 1.478 | |
| Platinum 1+ sweet-scented osmanthus 10 difficult to understand | 42±3.2 | 1 |
| Platinum 2+ sweet-scented osmanthus 20 difficult to understand | 77±3.2 | 0.627 | |
| Platinum 4+ sweet-scented osmanthus 40 difficult to understand | 95±2.9 | 0.332 | |
| Platinum 0.5+ sweet-scented osmanthus 7.5 difficult to understand | 47±3.5 | 0.575 | |
| Platinum 1+ sweet-scented osmanthus 15 difficult to understand | 72±3.2 | 0.5 | |
| Platinum 2+ sweet-scented osmanthus 30 difficult to understand | 92.9±2.9 | 0.3 |
MKN45 cell increment suppression ratio when independent medication of table 9 luteolin and the medication of associating oxaliplatin, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 5±3.2 | ||
| Sweet-scented osmanthus 5 | 12.5±3.1 | ||
| Sweet-scented osmanthus 10 | 46.2±3.5 | ||
| Sweet-scented osmanthus 20 | 67.22±3.2 | ||
| Sweet-scented osmanthus 40 | 80.88±2.9 | ||
| Platinum 1 difficult to understand | 30±3.2 | ||
| Platinum 2 difficult to understand | 45±3.5 | ||
| Platinum 4 difficult to understand | 52±3.5 | ||
| Platinum 8 difficult to understand | 69±3.5 | ||
| Platinum 0.5+ sweet-scented osmanthus 2.5 difficult to understand | 18±3.5 | 1.7 | |
| Platinum 1+ sweet-scented osmanthus 5 difficult to understand | 39±3.5 | 1 | |
| Platinum 2+ sweet-scented osmanthus 10 difficult to understand | 69±3.7 | 0.665 | |
| Platinum 4+ sweet-scented osmanthus 20 difficult to understand | 92±2.9 | 0.373 | |
| Platinum 0.5+ sweet-scented osmanthus 5 difficult to understand | 20.5±2.9 | 1.8 | |
| Platinum 1+ sweet-scented osmanthus 10 difficult to understand | 51±3.5 | 1 | |
| Platinum 2+ sweet-scented osmanthus 20 difficult to understand | 82±3.5 | 0.652 | |
| Platinum 4+ sweet-scented osmanthus 40 difficult to understand | 95±3.2 | 0.5 | |
| Platinum 0.5+ sweet-scented osmanthus 7.5 difficult to understand | 45±3.2 | 0.815 | |
| Platinum 1+ sweet-scented osmanthus 15 difficult to understand | 72±3.5 | 0.692 |
| Platinum 2+ sweet-scented osmanthus 30 difficult to understand | 92.8±2.8 | 0.472 |
Annotate: sweet-scented osmanthus=luteolin; Platinum=oxaliplatin difficult to understand
Suppression ratio %; Mean value SD, n=3
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Table 7-9 is presented near the zone (1: 5～1: 15) of this concentration ratio all good drug combination index, can show significantly that luteolin and oxaliplatin all have good drug combination effect to human large intestine cancer cell strain HCT116, human lung carcinoma cell line A549, human stomach cancer cell line MKN45.
Embodiment 8 luteolins are to the synergism of oxaliplatin on anti-transplant tumor
With the strain of B16 melanoma cell at In vitro culture after two generations, with 2 * 10
6Cell/only the be inoculated in female C57BL/6 of laboratory animal (body weight is about 20 grams) mice oxter is subcutaneous.Inoculate back second day random packet, and begin administration by the 0.1ml/10g body weight.Luteolin (Shaanxi plant development corporation, Ltd. of intelligent section), and with oxaliplatin (Sigma company product) with individually dosed, the test of different administering mode such as administering drug combinations grouping carrying out antitumor.Every group laboratory animal is 10.Measure the weight of animals before the administration, test and took off neck execution behind the title the weight of animals on 15th, strip tumor block organization and weigh.The mensuration of tumour inhibiting rate is by computing formula; Tumour inhibiting rate=(1-treatment group tumor weight/blank group tumor is heavy) * 100%.Calculate the heavy suppression ratio of tumor and carry out statistics (t check) processing.And calculate Q-value according to the Jin Shi formula.
Result of the test sees Table 10:
Table 10 separately when medication and the medication of associating oxaliplatin to transplanting the melanomatous animal test results of B16
| Grouping | Dosage mg/kg | The administration schedule | The rate of losing weight % | Heavy (g) the mean value SD of tumor | Tumour inhibiting rate % | Number of animals (only) beginning/end |
| Matched group platinum sweet-scented osmanthus difficult to understand sweet-scented osmanthus sweet-scented osmanthus platinum difficult to understand+sweet-scented osmanthus platinum+sweet-scented osmanthus difficult to understand | - 2 10 20 30 2+10 2+20 | 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 | ＜0 ＜5 ＜5 ＜5 ＜5 ＜5 ＜5 | 2.65±0.22 1.62±0.25 2.328±0.15 2.035±0.10 1.58±0.05 1.32±0.08 1.219±0.06 | 38.9 12.15 23.2 40 48 **# 54 **# | 10/10 10/10 10/10 10/10 10/10 10/10 10/10 |
| Platinum+sweet-scented osmanthus difficult to understand | 2+30 | 2-4，8-10 | ＜5 | 1.115±0.116 | 58 **# | 10/10 |
Sweet-scented osmanthus=luteolin; Platinum=oxaliplatin difficult to understand
Administering mode: oxaliplatin; The abdominal cavity, luteolin; Intraperitoneal administration
*Compare P＜0.01 with single with the oxaliplatin group
The #Q value shows summation action
Visible luteolin of result of the test and oxaliplatin have embodied tangible antitumor potentiation when share.Oxaliplatin+luteolin 10mg/kg, oxaliplatin+luteolin 20mg/kg, each group of oxaliplatin+luteolin 30mg/kg all has significant difference on the statistics with single comparing with the oxaliplatin group.Q-value also demonstrates has summation action.Animal test results has been supported the result of in vitro tests significantly, and promptly luteolin is to having apparent in view collaborative medication effect with oxaliplatin near the zone 1: 5～1: 15 concentration ratio.Change and can see from the weight of animals, each combination group is not seen has any toxicity to strengthen trend.
Comprehensive animal experiment as seen; Luteolin and oxaliplatin have good synergistic antitumor effect.
The synergism that embodiment 9 luteolins associating carboplatin suppresses in the human tumor cell line growth in vitro
Human lung carcinoma cell line cell A549 is suspended in the cell culture fluid that contains 10% (little) fetal bovine serum, with 5 * 10
3/ hole is seeded in 96 porocyte culture plates.After cultivating 24 hours, add luteolin (Shaanxi plant development corporation, Ltd. of intelligent section), and add in the culture fluid than mixing with variable concentrations with carboplatin (Sigma company product).Cultivate and make MTT mensuration after 72 hours.The suppression ratio of on cell proliferation carries out data analysis with CalcuSyn statistical software and drug combination exponential quantity (CI) method during with the dyeing of tetrazolium (MTT) method and the single usefulness of calculating and coupling luteolin and carboplatin.When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Cell proliferation inhibition rate when independent medication and drug combination, and the drug combination exponential quantity sees Table 11: the A549 cell increment suppression ratio when independent medication of table 11 luteolin and the medication of associating carboplatin, and drug combination index
| Single-dose thing activity (μ m) | Combination medicine activity (μ m) | Inhibitory rate of cell growth (%) | Drug combination coefficient value (CI) |
| Sweet-scented osmanthus 2.5 | 1±3.5 |
| Sweet-scented osmanthus 5 | 9±3.2 | ||
| Sweet-scented osmanthus 10 | 22±3.2 | ||
| Sweet-scented osmanthus 20 | 49±3.8 | ||
| Sweet-scented osmanthus 40 | 77±2.7 | ||
| Carboplatin 2.5 | 5±3.2 | ||
| Carboplatin 5 | 12±3.2 | ||
| Carboplatin 10 | 25±3.2 | ||
| Carboplatin 20 | 52±3.2 | ||
| Carboplatin 40 | 87±3.5 | ||
| Carboplatin 2.5+ sweet-scented osmanthus 2.5 | 7±3.2 | 1.16 | |
| Carboplatin 5+ sweet-scented osmanthus 5 | 32±3.2 | 0.8 | |
| Carboplatin 10+ sweet-scented osmanthus 10 | 59±3.9 | 0.915 | |
| Carboplatin 20+ sweet-scented osmanthus 20 | 87±2.7 | 0.97 | |
| Carboplatin 2.5+ sweet-scented osmanthus 5 | 12±2.7 | 1.17 | |
| Carboplatin 5+ sweet-scented osmanthus 10 | 42±2.7 | 0.96 | |
| Carboplatin 10+ sweet-scented osmanthus 20 | 72±3.5 | 1 | |
| Carboplatin 20+ sweet-scented osmanthus 40 | 92±3.2 | 0.88 | |
| Carboplatin 5+ sweet-scented osmanthus 2.5 | 17±3.2 | 1 | |
| Carboplatin 10+ sweet-scented osmanthus 5 | 59±3.2 | 0.7 | |
| Carboplatin 20+ sweet-scented osmanthus 10 | 82±3.2 | 0.82 | |
| Carboplatin 40+ sweet-scented osmanthus 20 | 92±2.8 | 0.88 |
Annotate: sweet-scented osmanthus=luteolin
Suppression ratio %; Mean value SD, n=3
When CI＜1, be synergism, during CI=1, be summation action; CI＞1 o'clock is antagonism.
Table 16 demonstrates at carboplatin with luteolin the molar concentration rate of the IC50 of A549 cell strain being about (1: 1), being presented near the zone (1: 2～2: 1) of this concentration ratio all has good drug combination index, can show significantly that with carboplatin and luteolin human lung carcinoma cell line A549 is had good drug combination effect.
Embodiment 10 luteolins associating carboplatin is to the antitumor synergism of transplanted tumor
With the strain of B16 melanoma cell at In vitro culture after two generations, with 2 * 10
6Cell/only the be inoculated in female C57BL/6 of laboratory animal (body weight is about 20 grams) mice oxter is subcutaneous.Inoculate back second day random packet, and begin administration by the 0.1ml/10g body weight.Luteolin (Shaanxi plant development corporation, Ltd. of intelligent section), and with carboplatin (Sigma company product) with individually dosed, unite and close different administering mode grouping carrying out antitumor test such as administration.Every group laboratory animal is 10.Measure the weight of animals before the administration, test and took off neck execution behind the title the weight of animals on 15th, strip tumor block organization and weigh.The mensuration of tumour inhibiting rate is by computing formula; Tumour inhibiting rate=(1-treatment group tumor weight/blank group tumor is heavy) * 100% calculates the heavy suppression ratio of tumor and carries out statistics (t check) and handle.And calculate Q-value according to the Jin Shi formula.
Result of the test sees Table 12
Table 12 separately when medication and the medication of associating carboplatin to transplanting the melanomatous animal test results of B16
| Grouping | Dosage mg/kg | The administration schedule | The rate of losing weight % | Heavy (g) the mean value SD of tumor | Tumour inhibiting rate % | Number of animals (only) beginning/end |
| Control group carboplatin sweet-scented osmanthus sweet-scented osmanthus sweet-scented osmanthus carboplatin+sweet-scented osmanthus carboplatin+sweet-scented osmanthus carboplatin+sweet-scented osmanthus | - 7 5 10 20 7+5 7+10 7+20 | 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 2-4，8-10 | ＜0 ＜5 ＜5 ＜5 ＜5 ＜5 ＜5 ＜5 | 2.65±0.22 1.65±0.25 2.535±0.22 2.328±0.15 2.035±0.10 1.35±0.07 1.23±0.07 1.018±0.126 | 37.7 4.3 12.15 23.2 49 **## 53.58 **## 61.58 **## | 10/10 10/10 10/10 10/10 10/10 10/10 10/10 10/10 |
Sweet-scented osmanthus=luteolin
Administering mode: carboplatin; The abdominal cavity, luteolin; Intraperitoneal administration
*Compare P＜0.01 with single with the carboplatin group
The #Q value shows summation action
The ##Q value shows synergism
Visible luteolin of result of the test and carboplatin have embodied tangible antitumor potentiation when share.Carboplatin+luteolin 5mg/kg, carboplatin+luteolin 10mg/kg, each group of carboplatin+luteolin 20mg/kg all has significant difference on the statistics with single comparing with the carboplatin group.Q-value also demonstrates has addition and synergism.Animal test results has been supported the result of in vitro tests significantly, and promptly luteolin is to having apparent in view collaborative medication effect with carboplatin near the zone 1: 2～2: 1 concentration ratios.Change and can see from the weight of animals, each combination group is not seen has any toxicity to strengthen trend.
Comprehensive animal experiment as seen; Luteolin and carboplatin have good synergistic antitumor effect.
Each above listed pertinent literature is all introduced the application as a reference with a full piece of writing.Many aspects involved in the present invention have been done as above and have been set forth.Yet, it should be understood that before not departing from spirit of the present invention to put that those skilled in the art can carry out equivalents and modification to it.Their scope is also included within the appended claim.
Claims (18)
1. luteolin or its officinal salt are a kind of medication combined with the purposes in the medicine of treatment tumor with platinum-based chemotherapy in preparation.
2. the purposes of claim 1, wherein said platinum-based chemotherapy medicine is selected from cisplatin, oxaliplatin and carboplatin.
3. the purposes of claim 2, wherein when described platinum-based chemotherapy medicine was cisplatin, described tumor was selected from melanoma, hepatocarcinoma, pulmonary carcinoma, colorectal cancer, gastric cancer, esophageal carcinoma and other solid tumors.
4. the purposes of claim 2, wherein when described platinum-based chemotherapy medicine was oxaliplatin, described tumor was selected from melanoma, colorectal cancer, pulmonary carcinoma, gastric cancer and other solid tumors.
5. the purposes of claim 2, wherein when described platinum-based chemotherapy medicine was carboplatin, described tumor was selected from melanoma, pulmonary carcinoma and other solid tumors.
6. pharmaceutical composition for the treatment of tumor comprises luteolin and a kind of platinum-based chemotherapy medicine of claim 1.
7. the pharmaceutical composition of claim 6, wherein said platinum-based chemotherapy medicine is selected from cisplatin, oxaliplatin and carboplatin.
8. the pharmaceutical composition of claim 7, wherein when described platinum-based chemotherapy medicine was cisplatin, the molar concentration rate of described cisplatin and luteolin was 1: 2.5 to 1: 10.
9. the pharmaceutical composition of claim 8, wherein said tumor is a solid tumor.
10. the pharmaceutical composition of claim 8, wherein said tumor is a melanoma.
11. the pharmaceutical composition of claim 7, wherein when described platinum-based chemotherapy medicine was oxaliplatin, the molar concentration rate of described oxaliplatin and luteolin was 1: 5 to 1: 15.
12. the pharmaceutical composition of claim 11, wherein said tumor are solid tumor.
13. the pharmaceutical composition of claim 11, wherein said tumor are melanoma.
14. the pharmaceutical composition of claim 7, wherein when described platinum-based chemotherapy medicine was carboplatin, the molar concentration rate of described carboplatin and luteolin was 1: 2 to 2: 1.
15. the pharmaceutical composition of claim 14, wherein said tumor are solid tumor.
16. the pharmaceutical composition of claim 14, wherein said tumor are melanoma.
17. arbitrary preparation of drug combination method of claim 6～16, this method comprise a kind of platinum-like compounds is mixed with the luteolin of claim 1.
18. the method for claim 17, wherein said platinum-like compounds is selected from cisplatin, oxaliplatin and carboplatin.
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| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
| CN101456881B (en) * | 2007-12-13 | 2012-10-17 | 北京嘉事联博医药科技有限公司 | Luteolin and platinum complexes of derivatives thereof, preparation method and use thereof |
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| US5789000A (en) * | 1994-11-14 | 1998-08-04 | Bionumerik Pharmaceuticals, Inc. | Sterile aqueous parenteral formulations of cis-diammine dichloro platinum |
| NZ510504A (en) * | 1998-09-25 | 2003-09-26 | Warner Lambert Co | Chemotherapy of cancer with acetyldinaline in combination with gemcitabine, capecitabine or cisplatin |
| US7326734B2 (en) * | 2003-04-01 | 2008-02-05 | The Regents Of The University Of California | Treatment of bladder and urinary tract cancers |
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| CN101456881B (en) * | 2007-12-13 | 2012-10-17 | 北京嘉事联博医药科技有限公司 | Luteolin and platinum complexes of derivatives thereof, preparation method and use thereof |
| CN102697768A (en) * | 2012-06-07 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of luteolin flavonoid compounds in preparation of anti-tumor medicaments |
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